Project Summary Accurate and efficient auditory perception relies on precisely organized and functionally specialized neuronal connections and synaptic circuits. The long-term goal of this research program is to elucidate the synaptic and cellular mechanisms whereby auditory circuits in the developing brain achieve their precise functional and structural organization. We investigate these mechanisms in the sound localization pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO). The MNTB-LSO pathway is a well- characterized, inhibitory, glycinergic pathway with a precise tonotopic organization. During development, the MNTB-LSO pathway undergoes a remarkable degree of reorganization, which significantly increases the precision of its tonotopic organization. This refinement occurs to a large degree before hearing onset and during the past funding period we have provided evidence that the precise temporal pattern of spontaneous activity before hearing onset plays a crucial role in this reorganization. This proposal seeks to investigate the synaptic mechanism whereby patterned activity exerts its effect on developing MNTB-LSO synapses to regulate tonotopic refinement. To approach this we will 1) characterized the mechanism underlying activity- dependent, patterned-sensitive long-term potentiation at inhibitory MNTB-LSO synapses before hearing onset, 2) elucidate the developmental role of GABA co-release from developing glycinergic MNTB-LSO synapses, and 3) characterize the effects of activity-dependent zinc release from developing MNTB-LSO synapses on synaptic transmission and reveal its role in circuit reorganization. To achieve these goals we will apply a broad repertoire of electrophysiological, imaging, and anatomical techniques to brain slices obtained from normal and genetically modified mice. Results from the proposed experiments will provide novel insight into basic mechanisms governing the formation of precisely organized auditory brain circuits. Information about these mechanisms is important to understand the biological causes that underlie developmental auditory processing deficits in humans, including central auditory processing disorder and developmental dyslexia, which are associated with abnormal auditory processing on the brainstem level.